In conclusion, our findings indicate that marijuana exposure in and of itself can serve as a risk factor that acts `above the genome' and can imprint upon the existing epigenetic landscape of adolescent neurodevelopment. Thus, the epigenetic effects of adolescent THC exposure may act in concert to augment future behavioral responses to drugs of abuse via stable and long-term regulation of genes at the transcriptional level. The results also support a novel role for the Penk gene as an emergent endogenous risk factor resulting from adolescent THC exposure, the dysregulation of repressive histone H3 methylation of which may underlie the long-term behavioral consequences of adolescent THC.